A ROLE FOR PAX-1 AS A MEDIATOR OF NOTOCHORDAL SIGNALS DURING THE DORSOVENTRAL SPECIFICATION OF VERTEBRAE

The notochord plays an important role in the differentiation of the pa raxial mesoderm and the neural tube. We have analyzed the role of the notochord in somite differentiation and subsequent formation of the ve rtebral column using a mouse mutant, Danforth's short-tail (Sd). In th is mutant, the skeletal phenotype is most probably a result of degener ation and subsequent loss of the notochord. The Sd gene is known to in teract with undulated (un), a sclerotome mutant. Double mutants betwee n Sd and un alleles show an increase in the severity of the defects, m ainly in the ventral parts of the vertebrae. We also show that part of the Sd phenotype is strikingly similar to that of the un alleles. As un is known to be caused by a mutation in the Pax-1 gene, we analyzed Pax-1 expression in Sd embryos. In Sd embryos, Pax-1 expression is red uced, providing a potential molecular basis for the genetic interactio n observed. A complete loss of Pax-1 expression in morphologically int act mesenchyme was found in the lower thoracic-lumbar region, which is phenotypically very similar to the corresponding region in a Pax-1 nu ll mutant, Undulated short-tail, The sclerotome developmental abnormal ities in Sd coincide closely, both in time and space, with notochordal changes, as determined by whole-mount T antibody staining. These find ings indicate that an intact notochord is necessary for normal Pax-1 e xpression in sclerotome cells, which is in turn required for the forma tion of the ventral parts of the vertebrae. The observed correlation a mong structural changes of the notochord, Pax-1 expression levels and skeletal phenotypes, suggests that Pax-1 might be an intrinsic mediato r of notochordal signals during the dorsoventral specification of vert ebrae.